Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1.
The synthetic rexinoid bexarotene (Targretin, LGD1069) inhibits the formation of both estrogen receptor-negative and estrogen receptor-positive breast cancer in preclinical models and controls the expression of growth-regulatory biomarkers, such as IGFBP-6 (insulin-like growth factor-binding protein 6), RARbeta, or cyclin D1. In this study, we identified a classical retinoic acid-responsive element in the first intron in the IGFBP-6 gene adjacent to a consensus AP-1 binding site, both elements essential for rexinoid-induced expression of IGFBP-6. In chromatin binding experiments, bexarotene increased the occupancy of the identified enhancer element by RXRalpha, RARbeta, cJun, cFos, and p300. In normal mammary epithelial cells and T47D breast cancer cells, small interfering RNA-mediated knockdown of all RXR isoforms or RARbeta, but not RARalpha or RARgamma alone, blocked the induction of IGFBP-6 by bexarotene. Simultaneous knockdown of RARalpha and RARgamma abrogated both the induction of RARbeta and the up-regulation and secretion of IGFBP-6. The suppression of either RARbeta or cJun by small interfering RNA blocked the recruitment of RXRalpha and cJun to the enhancer. These results demonstrate a novel cooperative interaction between retinoid receptors and AP-1 orchestrated by RARbeta and highlight a novel mechanism by which RARbeta can mediate the cancer-preventive effects of rexinoids.
Uray
Iván P
IP
Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121; Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121.
Shen
Qiang
Q
Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121; Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121.
Seo
Hye-Sook
HS
Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121.
Kim
HeeTae
H
Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121.
Lamph
William W
WW
Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121.
Bissonnette
Reid P
RP
Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121.
Brown
Powel H
PH
Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121; Breast Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and Ligand Pharmaceuticals Ltd., San Diego, California 92121. Electronic address: pbrown@breastcenter.tmc.edu.
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000077610:Bexarotene; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D016762:Genes, fos / Q000502:physiology; D006801:Humans; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000096:biosynthesis* / Q000235:genetics; D007438:Introns / Q000502:physiology; D042361:Mammary Glands, Human; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
D016588:Anticarcinogenic Agents; D000077610:Bexarotene; D019938:Cyclin D1; D018976:Insulin-Like Growth Factor Binding Protein 6; D016755:Proto-Oncogene Proteins c-jun; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; D018808:Transcription Factor AP-1; D050880:p300-CBP Transcription Factors; D000097768:Retinoic Acid Receptor gamma; C530104:CCND1 protein, human; C000607071:RARA protein, human; C082925:retinoic acid receptor beta